Both mammary cancer susceptibility QTL mapping in rats and low-penetrance breast cancer risk associated allele identification in humans are in early stages of discovery. Results of human population-based and rat genetic studies completed to date indicate that a majority of breast cancer risk alleles are low-penetrance, and pathways in addition to DNA repair and hormonal regulation control susceptibility. Furthermore, a majority of the risk associated polymorphisms that have been identified reside in non-protein coding DNA. Given the commonalities of low-penetrance, novel pathways, and non-protein-coding risk alleles, it is possible that there is some degree of overlap in susceptibility loci between these two organisms. There may be shared susceptibility loci that can be more easily identified in rats than by current human GWAS methods. If this is the case, resolving rat mammary carcinoma susceptibility QTLs to single loci so that the human orthologs can be extensively tested in human population-based genome-targeted association studies may continue to be fruitful. This was the case for Gould and colleagues who used rat Mcs5a
to successfully target the orthologous human genomic region to identify two breast cancer susceptibility alleles on human chromosome 9 
. Quan et al.
have shown that rodent susceptibility QTLs identified for a specific tumor type may also be useful to identify common susceptibility alleles for other tumor types 
. Thus, the amount of overlap between rodent and human common disease susceptibility loci may be appreciable.
Here, predicted rat mammary carcinoma susceptibility QTLs Mcs6
were physically confirmed using congenics. In our study Mcs2
, respectively, reduced the mammary carcinoma susceptibility phenotype of the WF strain by 70 and 50% when homozygous. In the original QTL studies, one Mcs2
COP or one Mcs6
WKy allele was predicted to reduce tumor multiplicity by 43% or 40%, respectively 
. While those studies were not completed using congenics, and we have not tested heterozygous females, comparing the results of tumor numbers of homozygous Mcs2
congenics with heterozygous females from the previous studies suggests there may be some degree of dominance from the WF allele at this locus. However, these differences may also be explained by background COP and WKy alleles that would have been present in females used for the QTL linkage studies. The stronger effect of the Mcs2
COP allele compared to the Mcs6
WKy allele may indicate that the Copenhagen strain has additional genetic variation within the region that contributes to reducing the Mcs phenotype.
In this study Mcs6
was mapped to a 33 Mb region from markers D7Rat171
, which corresponds to rat chromosome 7 base positions 22,382,725-55,364,398. The peak LOD scores for genetic markers in the predicted Mcs6
QTLs were at D7Mit28
, respectively 
. Both peak QTL markers fall within the narrowed interval confirmed here with congenics. D7Mit28
is at base position Chr7:
29,204,226, and D7Uwm11
is at base position Chr7:
50,160,469. This supports using QTL linkage analysis of rat complex phenotypes to identify regions of the genome on which to focus targeted human genome association studies.
Alignment of the rat Mcs6
QTL region to the human genome reference sequence revealed that the human orthologous region is entirely positioned on 34.2 Mb of chromosome 12,
and is inverted compared to rat Mcs6
. To our knowledge no polymorphisms in the human genome region orthologous to rat Mcs6
have shown a genome-wide significant association to breast cancer risk in a GWAS. An intriguing potential candidate gene in Mcs6
is insulin-like growth factor 1
). Human candidate-gene association studies that have tested IGF1
locus polymorphisms reported mixed results ranging from significant low-penetrance to null associations between IGF1
alleles and breast cancer risk 
. Increased IGF1 levels have been associated with breast cancer and increased breast cancer susceptibility 
. Common genetic variation in IGF1
has been associated with circulating levels of IGF1 in a population-based study 
. Other Mcs6
potential candidates have human orthologs that have been associated with cancer or other human diseases. SLC5A8
are predicted tumor repressor genes 
is predicted to be anti-angiogenic 
. A human genome-wide linkage analysis of posterior amorphous corneal dystrophy identified a region of human chromosome 12
that is orthologous to a Mcs6
region that contains genes DCN, LUM, KERA
, and EPYC 
has been shown to be upregulated in sporadic breast cancer biopsies in women of Mexican ancestry 
. Suppressor of cytokine signaling 2
) is also a promising potential candidate gene in Mcs6.
Higher SOCS2 levels have been associated with better breast cancer prognosis 
is an important mediator of prolactin regulated mammary gland development in the mouse 
is upregulated by 17β-estradiol in cancer cell lines 
, and SOCS2
expression was found to be higher in breast carcinomas compared to non-diseased breast tissue 
Mcs6 human orthologous transcripts that have been reported as differentially expressed between non-diseased breast tissue and ductal carcinoma tissue encode for two phosphatases (DUSP6, PPP1R12A), a proteoglycan (EPYC), a redox regulator (TXNRD1), and two uncharacterized proteins (ALX1, ZDHHC17). These findings suggest that the rat Mcs2 and Mcs6 QTLs control potentially novel mechanisms contributing to mammary cancer susceptibility that could translate to breast cancer.
Human genetic variation in the Mcs6 orthologous genomic region has been reported to be associated with breast cancer susceptibility, but tested polymorphisms have not reached genome-wide level significance. This highlights the importance of this region to breast cancer genetics. It suggests, as many have, that Bonferroni correction based methods may be too stringent to control for multiple comparison testing in human population-based association studies. The confirmed rat Mcs2 and Mcs6 QTLs support that some or all of the potential human breast cancer risk associations are true positives and warrant further investigation.
We conclude that the human genomic region on chromosome 12 from base positions 71,270,266 - 105,502,699 is orthologous to rat Mcs6. This region may be a good target for extensive population-based genetic association studies to determine if humans have a concordant breast cancer susceptibility allele. Rat Mcs6 and Mcs2 congenic lines will be useful to study breast cancer genetic susceptibility mechanisms.